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=Human eIF2α (1q8k)=

=Introduction= The translation of proteins requires three steps to occur; initiation, elongation and termination. With each step one or more factors is involved in aiding the process. In eukaryotes initiation has the most factors that are essential for initiation to occur. eIF2 is one of the many initiating factors needed for eukaryotic initiation to occur. It is needed for proper initiation to occur. It initially binds to eIF2β in the presence of GTP. It then binds to Met-tRNAmeti and releases the eIF2β. This specific eIF2(1q8k) is the human eIF2α.

=Structure= The human eIF2 structure was determined by NMR spectroscopy. The human eIF2 structure is a small structure made of two domains. These two domains have a unique characteristic in that they are mobile relative to the other domain. The N terminal domain (NTD) of the structure was discovered in previous years. The NTD is a β-barrel containing five anti-parallel β strands in an oligo-nucleotide binding domain(OB) fold. The Ser-51 is where the phosphorylation/dephosphorylation occurs, which is found on the loop connecting β3 and β4 in the OB domain. The second domain of the N terminus is a helical domain and it follows directly after the OB domain. The first helix of this domain has large quantities of interactions, including a disulfide bridge, which allows adaptation of its orientation with respect to the OB domain. The connection of the two domains is a likely site for protein-protein binding due to the highly conserved residues and negatively charged groove. The C-terminal domain (CTD ) for the human eIF2 was undetermined until the whole structure was discovered. The CTD contains a αβ-fold, which remarkably has a similar appearance to the CTD of eEF1Bα, a translation elongation factor, even though there is no sequence homology between the two. eIF2α also has a topology of ββαββαβ, which is the same as eEF1Bα. =Function= The eIF2α subunit is considered to function primarily as a regulatory element of eIF2. The eIF2α is also linked to the binding of Met-tRNAimet and eIF2γ. It was determined as well that in fact eIF2α was need for tight binding of eIF2γ and Met-tRNAimet. This is seen by the shortened lengths of beta strands β7 and β8 which allow room for binding of both tRNA and eIF2α. This is supported by genetic and biochemical assays done by Roll-Mecak which showed mutation around the putative adenine binding pocket did not affect the binding of eIF2α but did affect the binding of Met-tRNAimet. The eIF2α is also the target of many kinases which become actived when the cell undergoes certain stresses. These kinases include PKR which is activated by virus infection, the heme regulated inhibitor(HRI) which is activated by iron deficiency, PERK which is activated by increased amounts of unfloded proteins in the ER, and GCN2 which is activated by amino acid starvation. As well, Ser51 has been identified as a phosphorylation site for these kinases. When phosporylation of Ser51 occurs it results in a strong inhibition of translation initiation. This is caused by an increased affinity for eIF2B, which results in a decreased GDP/GTP exchange rate for eIF2, and therefore a decreased population of activated GTP-bound eIF2.

=References=